Review ArticlePhenotypic and Functional Diversities of Myeloid-DerivedSuppressor Cells in Autoimmune Diseases

Huijuan Ma1 and Chang-Qing Xia 2

1Department of Nephrology, Jining No. 1 People’s Hospital, Jining 272011, China2Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville,FL 32610, USA

Correspondence should be addressed to Chang-Qing Xia; cqx65@yahoo.com

Received 7 September 2018; Accepted 9 December 2018; Published 23 December 2018

Guest Editor: Qingdong Guan

Copyright © 2018 Huijuan Ma and Chang-Qing Xia. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original workis properly cited.

Myeloid-derived suppressor cells (MDSCs) are identified as a heterogeneous population of cells with the function to suppressinnate as well as adaptive immune responses. The initial studies of MDSCs were primarily focused on the field of animal tumormodels or cancer patients. In cancer, MDSCs play the deleterious role to inhibit tumor immunity and to promote tumordevelopment. Over the past few years, an increasing number of studies have investigated the role of MDSCs in autoimmunediseases. The beneficial effects of MDSCs in autoimmunity have been reported by some studies, and thus, immunosuppressiveMDSCs may be a novel therapeutic target in autoimmune diseases. There are some controversial findings as well. Manyquestions such as the activation, differentiation, and suppressive functions of MDSCs and their roles in autoimmune diseasesremain unclear. In this review, we have discussed the current understanding of MDSCs in autoimmune diseases.

1. Introduction

Myeloid-derived suppressor cells (MDSCs) started to bedescribed more than three decades ago mainly in cancer[1, 2]. The suppressive effects of MDSCs on immuneresponses lead to the failure of immune surveillance of cancerand promotion of tumor angiogenesis and metastasis. Thus,MDSCs are suggested to be an important cell componentfor creating tumor immunosuppressive microenvironment[3–7]. In recent years, it has been reported about the involve-ment of MDSCs in a variety of inflammatory disorders,including autoimmune diseases [8–12]. MDSCs serve as thenegative regulator of immune responses, and they are likelyto play a protective role in autoimmune diseases by inhibitingT cell-mediated immune responses. Most of the studies ofMDSCs in autoimmunity are carried out in animal experi-ments, and some findings are controversial. The real biolog-ical and pathological roles of MDSCs in autoimmunediseases still need to be further characterized. In this review,we summarize the origin, phenotype, and functional

characteristics of MDSCs and their involvement in autoim-mune diseases as well as MDSCs as potential targets for ther-apeutic intervention.

2. Origin, Phenotype, and FunctionalCharacteristics of MDSCs

Common myeloid precursor cells derive from hematopoieticstem cells (HSCs) in the bone marrow, and they give rise to“immature myeloid cells” (IMCs) without suppressive fea-tures in an unactivated state [13]. In healthy individuals,IMCs can differentiate into mature, functional dendritic cells(DCs), macrophages, and granulocytes [14]. However, in cer-tain pathologic conditions, such as inflammation, tumors,infections, trauma, transplants, sepsis, or autoimmune dis-eases, the differentiation of IMCs is impaired, and subse-quently, IMCs are activated and proliferate in response todiverse endogenous and exogenous factors [13, 15–17]. Asa result, IMCs differentiate into MDSCs, resulting in the dra-matic expansion and accumulation of a large number of

HindawiMediators of InflammationVolume 2018, Article ID 4316584, 8 pageshttps://doi.org/10.1155/2018/4316584

MDSCs in peripheral tissues. MDSCs can potently inhibitimmune responses through the expressions of suppressivefactors [13].

In mice, MDSCs are characterized by the coexpression ofCD11b and Gr-1. The CD11b+Gr-1+ cell population isdivided into two relatively distinct subsets: M-MDSCs(CD11b+Ly6ChiLy6G-) with monocytic morphology andG-MDSCs (CD11b+Ly6ClowLy6G+) with granulocytic mor-phology [18]. Recently, the expressions of CD115, CD80,CD124, F4/80, CD16, and CD31 have also been suggestedas markers for identifying MDSCs, although these markersare not specific for MDSCs [19, 20].

Different from murine MDSCs, most human MDSCsexpress both CD11b and CD33 and have an absent or lowexpression of HLA-DR. Therefore, human MDSCs can begenerally defined as CD11b+CD33+HLA-DRlow/-. Withinthis population, monocytic MDSCs and granulocytic MDSCscan be further characterized by the phenotype of CD14+-

CD15low/- and CD14-CD15+CD66b+, respectively, whichseems to be consistent with hematologic morphology [13,21]. Given the heterogeneity of MDSCs populations and thedifferent combinations of markers used, there may be someoverlap between the subsets of MDSCs, and these classifica-tions are somewhat controversial [22, 23]. In a recent study,a high level of lectin-type oxidized LDL receptor 1 (LOX-1)was identified in polymorphonuclear MDSCs (PMN-MDSCs) in the peripheral blood and tumor tissues of cancerpatients, which was associated with endoplasmic reticulumstress and lipid metabolism [24]. Lately, another studyshowed that the phenotypic and functional characteristicsof MDSCs can shift at different clinical stages of multiplesclerosis (MS) [25].

MDSCs require different signals for their expansionand activation. A variety of factors play important rolesin the expansion of MDSCs such as cyclooxygenase-2(COX-2), prostaglandin E2 (PGE2), granulocyte/macrophagecolony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), IL-6, IL-3, vascular endothelialgrowth factor (VEGF), and stem cell factor (SCF)-1 [13,26–29]. The activation of MDSCs is associated with IFN-γ,TGF-β, IL-13, IL-4, etc. [13]. These factors can trigger signal-ing pathways in MDSCs which are involved in regulating theprocesses of cell differentiation, proliferation, and apoptosisduring hematopoiesis [30–32].

MDSCs can suppress the immune response through avariety of different mechanisms, including close cell-cell con-tact and soluble mediators, of which the predominant factorsare arginase-1 (Arg-1) and inducible nitric oxide synthase(iNOS) [33]. The expressions of Arg-1 and iNOS which gen-erate NO responsible for theMDSCs suppressive function areupregulated by activated MDSCs. The common substrateof Arg-1 and iNOS is L-arginine. Reactive oxygen species(ROS) represent another important mechanism [13, 34–37].The monocytic MDSCs mainly associated with inflammationwere found to express high levels of iNOS and low levels ofROS, whereas the granulocytic MDSCs mainly associatedwith tumors expressed high levels of ROS and low levels ofiNOS [13]. Both subsets expressed Arg-1 [18, 38]. In addi-tion, indoleamine 2,3-dioxygenase (IDO), IL-10, PGE2,

COX-2, program death ligand 1 (PD-L1), and TGF-β alsoare very important to enable MDSCs to inhibit T cell prolif-eration and cytotoxicity [39–42]. MDSCs also facilitate regu-latory T cells (Tregs) to exert suppressive functions. It hasbeen shown that Gr-1+CD115+ MDSCs can promote thedevelopment of Foxp3+ Tregs in vivo and mediate the inacti-vation of tumor-specific T cells in a tumor mouse model [43].Further studies are required to demonstrate whether MDSCsare involved and associated with Tregs in a common immuneregulatory network. Moreover, a recent study found thatLy6G+ PMN-MDSCs could control the selective accumula-tion and cytokine secretion of B cells in the central nervoussystem (CNS), which facilitated the recovery of disease inexperimental autoimmune encephalomyelitis (EAE) [44].The relationship between MDSCs and B cells also remainsto be further studied.

3. The Role of MDSCs in Autoimmunity

MDSCs’ function has mostly been studied in animaltumor models and cancer patients. Recently, a growingbody of evidence has suggested that MDSCs may beactively participating in the development of autoimmunediseases, such as MS [8, 25, 45], systemic lupus erythema-tosus (SLE) [11, 46], type 1diabetes (T1D) [47], inflamma-tory bowel disease (IBD) [9, 48], and rheumatoid arthritis(RA) [49]. However, the in vitro and the in vivo studies aresometimes controversial.

3.1. In Vitro Study of MDSCs. Generally speaking, in vitro,CD11b+Gr-1+ cells isolated from autoimmune inflammatorysites are able to inhibit T cell proliferation, typically throughthe participation of iNOS and Arg-1. In the autoimmunehepatitis (AIH) mouse model, the accumulation of CD11b+-

Gr-1+ myeloid cells was observed in the BALB/c Tgfb1-/-liver.And only the isolated Ly6Chi subset was able to efficientlysuppress CD4+ T cell proliferation in vitro by several differ-ent mechanisms, including NO, IFN-γ, and cell-cell contact[50]. Similarly, in the IBD mouse model, CD11b+Gr-1+ mye-loid cells accumulated in the spleens and secondary lym-phoid tissues, and only CD11b+Ly6ChiLy6G- MDSCssuppressed the proliferation and production of cytokines byCD4+ T cells, which were mediated by NO, cell-cell contact,and partially by IFN-γ and PGs [48]. It was shown thatCD11b+Ly6ChiLy6G- MDSCs isolated from the spleen afterEAE were induced potently inhibited CD4+ and CD8+ T cellproliferation, and induced apoptosis of proliferating T cellex vivo, which was mediated by iNOS activity [8]. In line withthese findings, MDSCs were also involved in experimentalautoimmune uveoretinitis (EAU). These cells expressedCD11b phenotypically resembling monocytes and were accu-mulated in the inflamed eyes. In vitro, T cell proliferationcould be greatly suppressed by these isolated monocyte-likecells [51]. Subsequent research in EAU showed that the intactTNF response axis was responsible for the suppressive func-tion of MDSCs [52]. In line with the above reports, CD11b+-

Gr-1low MDSCs were also identified in lupus-prone MRL-Faslpr mice that develop autoimmune organ damages. Thesecells had a suppressive effect on CD4+ T cell proliferation

2 Mediators of Inflammation

ex vivo, and Arg-1 inhibitor could block the suppression,indicating that arginase served as the dominant suppressivefactor of MDSCs in this autoimmune setting [11]. Recently,in the pristane-induced lupus mouse model, we observed thatCD11b+Ly6Chi monocytes sorted from the peritoneal cellsgreatly inhibited T cell proliferation ex vivo which was medi-ated by cell-cell contact, NO, and PGE2 and could inhibitTh1 differentiation but enhanced the development of Tregs[53]. Our findings provide a novel insight into the role ofLy6Chi monocytes mobilized by pristane injection in thepathogenesis of pristane-induced lupus in mice. We believethe Ly6Chi monocytes induced by pristane injection aremonocytic MDSCs.

3.2. In Vivo Study of MDSCs. Despite that MDSCs canpotently inhibit T cell responses in vitro, the presence ofMDSCs in autoimmune diseases is different, and currentstudies have shown conflicting roles for MDSCs in auto-immunity, either as an aggravating or as a curative factorof disease.

EAE is a common mouse model for multiple sclerosis,which is an autoimmune inflammatory neurological disease.Several studies have tried to demonstrate the possible role ofMDSCs in EAE. King et al. observed that CD11b+CD62L+-

Ly6Chi cells were mobilized increasingly and accumulatedin the blood and CNS before clinical episodes of the disease,and these cells were subsequently matured into inflammatorymacrophages and/or functional DCs. Thus, the study con-cluded that the accumulation of CD11b+Ly6Chi monocytesin vivo served as pathologic effectors and was associated withEAE pathogenesis [45]. Similarly, the Mildner study showedthat the selective depletion of CCR2+Ly6Chi monocytesstrongly reduced the CNS autoimmunity, indicating adisease-promoting role of CCR2+Ly6Chi monocytes duringautoimmune inflammation of the CNS [54]. Yi et al. alsoconfirmed that the expansion of CD11b+Gr-1+ cells waspresent in the development of EAE. Although these MDSCsinhibited T cell proliferation, they promoted inflammatoryTh17 cell differentiation in vitro mediated by IL-1β. Selectivedepletion of MDSCs using gemcitabine resulted in a markedreduction in the severity of EAE, and the adoptive transfer ofMDSCs after this treatment restored EAE disease progres-sion. The authors also demonstrated that the severity ofEAE was correlated with the frequency of Th17 cells andthe levels of inflammatory cytokines [55]. All the above find-ings in EAE indicate that MDSCs in vivo serve as pathologiceffectors. However, some other studies had different conclu-sions about the activity of MDSCs. Ioannou et al. reportedthat before the disease remission, CD11bhiLy6G+Ly6C-

granulocytic MDSCs were abundantly accumulated in theperipheral lymphoid organs. Adoptive transfer of G-MDSCspotently delayed the development of EAE through the sup-pressive effect on the priming of Th1 and Th17 cells. Theupregulation of PD-L1 upon exposure to the autoimmunemilieu both in vitro and in vivo was essential for the suppres-sive function of G-MDSCs [56]. Taken together, it seems thatMDSCs have opposite roles in EAE, having both inflamma-tory functions and protective functions. The discrepancy ofdifferent reports suggests that further characterization of

MDSCs in various autoimmune settings is needed. It is alsopossible more functionally diverse MDSCs subsets may exist.

Lately, MDSCs have been involved in the development ofSLE associated with organ damages. A study reported thatthe deletion of CD24 in a lupus-like disease model drivenby heat shock proteins (HSPs) led to the increase of CD11b+-

Gr-1+ MDSCs and Tregs that augmented immune tolerance,accompanying with the alleviation of lupus-like renal pathol-ogy [57]. On the contrary, it was recently shown that in ahumanized SLE model MDSCs contributed to induce Th17responses and related renal damage which was dependenton Arg-1 [58]. In addition, a recent study demonstrated thatthere were gender differences about the cellular and func-tional characteristics of myeloid cells in (NZB×NZW) F1mice. The greatly increased Gr-1hiLy6G+CD11b+ myeloidcells in male mice were capable of inhibiting autoantibodyproduction and IL-10 production and slowing the progres-sion of lupus-like disease in vivo. Furthermore, the produc-tion of antinuclear autoantibodies was increased after anti-Gr-1 mAb treatment. In vitro Gr-1hiCD11b+ cells coulddirectly inhibit B cell differentiation. The authors postulatedthat these cells represented an important inhibitory mecha-nism in male mice and involved in SLE pathogenesis [59].In Roquinsan/san SLEmice, sortedMDSCs induced the expan-sion of IL-10-producing regulatory B cells in vitro via NO.After administration of MDSCs, the regulatory B cells inthe spleens of Roquinsan/san mice were expanded but effectorB cells were decreased, accompanied with the reduction ofserum anti-dsDNA antibody levels and the improvement ofrenal pathology. Therefore, MDSCs were likely to be apromising therapeutic target in the pathogenesis of SLE[46]. In our in vivo experiment, the transfer of purifiedCD11b+Ly6Chi pristane-induced peritoneal monocytes wasable to greatly inhibit anti-keyhole limpet hemocyanin(KLH) antibody production induced by KLH immuniza-tion [53], suggesting that these cells may have a protectiveeffect in chronic autoimmune inflammation in pristane-induced lupus.

The role for MDSCs in T1D has been recently studied.The expanded Gr-1+CD11b+ MDSCs induced by anti-CD20 treatment in a mouse model of diabetes were foundto suppress T cell proliferation dependent on NO, IL-10,and cell-cell contact and induce Tregs differentiation viaTGF-β. In vivo, the transient expansion of MDSCs inducedby anti-Gr-1 treatment delayed the development of diseasein NOD mice. These findings suggested that Gr-1+CD11b+

MDSCs contributed to establish immune tolerance and couldbe a novel immunotherapeutic target for T1D [47]. A recentstudy found that CD11bhiGr-1int MDSCs were significantlyincreased in the peripheral blood of diabetic NOD mice.The authors suggested that the expansion of MDSCs wasinvolved in the onset of diabetes [60]. Another study demon-strated that the adoptive transfer of MDSCs had an Ag-specific suppressive function and could prevent the onset ofT1D through the induction of CD4+CD25+Foxp3+ Tregsdevelopment and anergy in autoreactive T cells [61].

MDSCs were also described in other autoimmune dis-eases. In the mouse model of IBD induced in VILLIN-hemagglutinin (HA) transgenic mice, the significantly

3Mediators of Inflammation

increased CD11b+Gr-1+ MDSCs in the spleen and intestinewere found to induce T cell apoptosis and suppress T cellproliferation ex vivo in a NO-dependent manner as well. Fur-thermore, the isolated CD11b+Gr-1+ MDSCs inhibited Tcell-mediated colitis in VILLIN-HA mice [9]. The isolatedgranulocytic MDSCs from the spleens in a collagen-inducedarthritis (CIA) mouse model were found to inhibit CD4+ Tcell proliferation in vitro. Moreover, these cells could sup-press the differentiation of CD4+ T cells into Th17 cells.Adoptive transfer of MDSCs reduced the severity of jointinflammation in vivo, and the removal of MDSCs wors-ened the disease [49]. Another recent study found thatCD11c-CD11b+GR-1+ MDSCs separated from the periph-eral blood and spleens of CIA mice could inhibit T cell pro-liferation in vitro partly via IL-10 and Arg-1, and in vivoinfusion of MDSCs significantly ameliorated rheumatoidinflammation [62]. Alopecia areata is an autoimmune skindisease, the characteristic of which is inflammatory immuneresponses that cause hair loss. In a mouse model of alopeciaareata, Gr-1+CD11b+ MDSCs were capable of inhibiting Tcell proliferation in vitro, and subsequent in vivo applicationled to partial restoration of hair growth [63]. MDSCs werealso described in a mouse model of experimental autoim-mune myasthenia gravis (EAMG), in which the adoptivetransfer of MDSCs was found to effectively reverse thedisease progression [64]. Further analysis showed thatin MDSCs-treated EAMG mice, acetylcholine receptor-(AChR-) specific immune responses were suppressed, serumanti-AChR IgG levels were decreased, and complement acti-vation was reduced, in which various immune-modulatingfactors, such as PGE2, iNOS and arginase, were activelyinvolved [64].

Up to date, almost all studies about MDSCs in humanfocus on cancer. There are few about MDSCs in patients withautoimmune diseases. A study performed in T1D patientshas shown that in peripheral blood mononuclear cells(PBMC) the frequency of CD11b+CD33+ MDSCs is signifi-cantly increased, but these MDSCs are not maximally sup-pressive in function, suggesting that functional defects inMDSCs may contribute to T1D pathogenesis [60]. Recently,a study on human SLE demonstrated the pathogenic role ofMDSCs. Compared to healthy controls, HLA-DR-CD11b+-

CD33+ MDSCs in the peripheral blood of active SLE patientssignificantly increased. A positive correlation between thefrequency of MDSCs and Th17 responses, serum Arg-1 level,and disease severity was observed, which provided newinsights into the molecular mechanism targeting MDSCsfor the treatment of SLE [58]. This increase of HLA-DR-CD11b+CD33+ MDSCs may be mobilized and recruitedduring the active inflammatory process in SLE, becauseinflammation can lead to myelopoiesis [65] potentially givingrise to these intermediate stages of myeloid cells. Addition-ally, the numbers of MDSCs in the peripheral blood andplasma Arg-1 level were greatly increased in RA patients.The elevated frequency of Th17 cells in those patients wasobserved to be negatively correlated with the plasma Arg-1level and the frequency of MDSCs. It was also found thatthere was a negative correlation between the level of plasmaTNF-α and MDSCs frequency [66]. Recently, another study

about RA patients has shown that the expansion of MDSCsas a risk factor was associated with disease activity and jointinflammation [67]. Given the important role of MDSCs inmodulating immune response, more research needs to becarried out to explore the effect of MDSCs in human autoim-mune disorders.

In conclusion, MDSCs possess a variety of activities inautoimmune models and diseases (summarized in Table 1);it is therefore a challenge to draw a definitive conclusionon the roles of MDSCs in autoimmune diseases [68, 69].Generally speaking, in vitro, the isolated CD11b+Gr-1+

MDSCs from inflammatory sites inhibit T cell responsesdependent on various mechanisms such as NO and Arg-1.However, in vivo, endogenous MDSCs may be proinflam-matory and fail to effectively reduce the severity of autoim-mune diseases in several systems (e.g. in EAE [45, 54, 55]).By contrast, the adoptive transfer of MDSCs is able toinduce immune tolerance to self-Ag and limits autoimmunepathology and has a beneficial effect on the autoimmunedisease, as observed in models of IBD [9], T1D [61], andinflammatory eye disease [70]. The reasons that lead to thesediscrepancies between the activities of endogenous andexogenous MDSCs remain unclear. A possible explanationmay be that certain factors coexisting in the same inflamma-tory microenvironment inhibit the suppressive activity ofMDSCs, and the isolation of MDSCs is liberated from this“inhibitory” environment and MDSCs regain their immuno-suppressive function upon readministration or addition intoin vitro culture systems.

4. Therapeutic Potential of MDSCs inAutoimmune Diseases

The application of MDSCs exogenously in certain animalmodels shows great efficacy in suppressing autoimmune dis-eases, indicating that MDSCs might be a promising cellularimmunotherapeutic target in autoimmune diseases. Severalpotential cellular sources are available for in vitro generatedMDSCs. Exogenous MDSCs isolated from the peripheralblood or bone marrow could be markedly expandedin vitro by use of growth factor/cytokine regimens [71–73].In addition, it has been reported that exogenous MDSC pop-ulations also can derive from hematopoietic stem cells andembryonic stem cells [74]. More recently, the monocytes iso-lated from the peripheral blood were cultured in vitro supple-mented with PGE2, for the generation of high numbers ofMDSCs, and their functional stability was established [75].In vitro generated MDSCs share many characteristics withtheir ex vivo isolated counterparts. They have strong sup-pressive effect on the proliferation of CD4+ and CD8+ T cellsmediated by the expressions of iNOS and/or Arg-1 and cell-cell contact [72]. All these methods above will be able to pro-vide reliable cellular products for immunotherapy in treatingautoimmune diseases. Several groups have shown that theadoptive transfer of ex vivo generated MDSCs had the abilityto inhibit graft-versus-host disease (GVHD) and preventallograft rejection in mice [73, 74, 76]. Meanwhile, there aresome potential risks associated with the utilization of MDSCsto treat autoimmune diseases. For example, MDSCs utilized

4 Mediators of Inflammation

would be nonspecific for antigen-specific T cells. Therefore,the suppressive effects of MDSCs on harmful T cellresponses for autoantigens and the protective immuneresponses to pathogenic microorganisms or tumors existat the same time. It would also be difficult to control themigration and accumulation of the injected MDSCs. Addi-tionally, the release of inflammatory factors may occur afterthe administration of MDSCs. Some other unpredictablerisks may also exist. Thus, more extensive research inanimal models is indispensable before MDSCs therapymoves into clinical studies.

5. Concluding Remarks

MDSCs are a highly heterogeneous cell subpopulation. Theyhave multifaceted phenotypic characteristics and may sup-press T cell proliferation through various mechanisms.Large numbers of factors are involved in the differentiation,migration, expansion, and activation of MDSCs. However,

there are many unresolved questions in the field of MDSCsresearch. Up to now, the biological roles of MDSCs arerarely known. The role of endogenous MDSCs in autoim-mune diseases in vivo remains controversial. Many ques-tions about the variety of activities for MDSCs remain tobe elucidated. It is necessary to understand why the induc-tion and suppressive mechanisms of MDSCs are differentbetween in vivo and in vitro environments. A better com-prehension of the role of human MDSCs in autoimmunityand how to manipulate this cell population in patients withautoimmune diseases will be of great clinical significance.Importantly, exogenously prepared MDSCs have a greatpotential to become an effective immunotherapeutic regi-men for autoimmune diseases.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Table 1: Myeloid-derived suppressor cells in autoimmune diseases.

Disease Species Phenotype Mechanism of suppression (in vitro) Effect in vivo Reference

Multiple sclerosis

Mouse CD11b+Ly6ChiLy6G- NO apoptosis Not determined [8]

Mouse CD11b+CD62L+Ly6C+ Undetermined Proinflammatory [45]

Mouse CCR2+CD11b+Ly6Chi Unknown Increase severity [54]

Mouse CD11b+Gr-1+ IL-1β Increase severity [55]

Mouse CD11bhiLy6G+Ly6C- PD-L1 Reduce severity [56]

Systemic lupus erythematosus

Mouse CD11b+Gr-1low Arginase-1 Not determined [11]

Mouse CD11c-CD11b+Gr-1+ NO Suppressor [46]

Mouse CD11b+Ly6Chi NO, PGE2, cell-cell contact Possibly protective [53]

Human HLA-DR-CD11b+CD33+ Unknown Increase severity [58]

Mouse Gr-1hiLy6G+CD11b+ ROS, NOSuppressor (in

males)[59]

A lupus-like disease drivenby HSP

Mouse CD11b+Gr-1+ Unknown Reduce severity [57]

Type 1 diabetes

Mouse CD11b+Gr-1+ NO, IL-10, cell-cell contact Reduce severity [47]

Mouse CD11bhiGr-1int Cell-cell contact Proinflammatory [60]

Human HLA-DR-CD11b+CD33+ Cell-cell contact Proinflammatory [60]

Mouse Gr-1+CD115+MHC class II-restricted Ag

presentationReduce severity [61]

Inflammatory bowel diseaseMouse CD11b+Gr-1+ NO apoptosis Reduce severity [9]

Mouse CD11b+Ly6ChiLy6G- NO, cell-cell contact,partially IFN-γ, PGs

Not determined [48]

Rheumatoid arthritis

Mouse CD11b+Ly6G+Ly6Clow Arg-1, NO Reduce severity [49]

Mouse CD11c-CD11b+GR-1+ IL-10, Arg-1 Reduce severity [62]

Human HLA-DR-CD11b+CD33+ Unknown Suppressor [66]

Human CD11b+CD33+HLA-DR- Unknown Increase severity [67]

Inflammatory eye diseaseMouse CD11b+Gr-1+Ly6G- TNFR-dependent, arginase Not determined [51, 52]

Mouse CD11b+Gr-1+ IL-6 Reduce severity [70]

Autoimmune hepatitis Mouse CD11b+Ly6ChiLy6G- NO, IFN-γ, cell-cell contact Not determined [50]

Alopecia areata Mouse CD11b+Gr-1+ T cell apoptosis Possibly protective [63]

Experimental autoimmunemyasthenia gravis

Mouse CD11b+Gr-1+ PGE2, NO, Arg-1 Reduce severity [64]

5Mediators of Inflammation

Acknowledgments

This review is supported by the Shandong Science andTechnology Development Plan on Medicine and Hygienein China (2017WS147) and the National Natural ScienceFoundation of China (No. 81803097).

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